otamixaban and Coronary-Thrombosis

Otamixaban, under development by sanofi-aventis, is a directly activated Factor X (FXa) inhibitor that is currently in phase IIb clinical trials for acute coronary syndrome and myocardial infarction. Preclinical studies with otamixaban demonstrated high selectivity of the compound for FXa. Otamixaban effectively inhibited thrombin generation without interfering with existing thrombin activity. Intravenously administered otamixaban was well tolerated in both male and female patients, independent of age. Otamixaban exhibited a well-described dose-exposure relationship, a low inter-patient variability in plasma exposure, and was both rapidly distributed in the plasma and quickly eliminated. The rapid decrease in otamixaban plasma concentrations following the termination of an infusion is an advantage over other FXa inhibitors that have longer half-lives. Otamixaban exhibited an improved pharmacodynamic profile over conventional anticoagulant therapies such as heparin. During clinical trials with otamixaban, no major drug interactions were observed with agents that were likely to be used in combination therapy. Otamixaban is a promising agent that merits further consideration for clinical trials in patients with coronary thrombosis.

Topics: Animals; Anticoagulants; Clinical Trials, Phase II as Topic; Coronary Thrombosis; Cyclic N-Oxides; Factor Xa Inhibitors; Humans; Myocardial Infarction; Pyridines; Structure-Activity Relationship

We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt-PA-induced coronary thrombolysis. Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 microg kg(-1)+1, 3, or 10 microg kg(-1) min(-1), respectively; n=8 per dose), heparin (60 u kg(-1)+0.7 u kg(-1) min(-1), n=8), or RPR109891 (30 microg kg(-1)+0.45 microg kg(-1) min(-1), n=8), was initiated. Aspirin (5 mg kg(-1), i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt-PA was administered (100 microg kg(-1)+20 microg kg(-1) min(-1) for 60 min). The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23+/-5 min for FXV673 versus 41+/-11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05). Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose-dependent manner. Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively. In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt-PA-induced coronary thrombolysis.

Topics: Animals; Anticoagulants; Blood Coagulation; Coronary Circulation; Coronary Thrombosis; Cyclic N-Oxides; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Heparin; Male; Partial Thromboplastin Time; Peptides; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Prothrombin; Prothrombin Time; Pyridines; Recombinant Proteins; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator; Treatment Outcome; Vascular Patency